Isopropenylmercapto-3-alpha-acylamino-azetidin-4-ones

ABSTRACT

1 - R2 - 2A - ISOPROPENYLMERCAPTO - 3A - N - AC-AMINOAZETIDIN-4-ONES OF THE FORMULA   2-(CH3-C(=CH2)-S-),3-(AC-NH-),4-(O=),1-R2-AZETIDINE   WHEREIN R2 REPRESENTS A HYDROGEN ATOM OR A FORMYL GROUP AND AC REPRESENTS THE ACYL RADICAL OF AN ORGANIC ACID, SHOW ANTIBACTERIAL PROPERTIES, BUT ARE PRIMARILY USEFUL AS INTERMEDIATES.

United States Patent ABSTRACT OF THE DISCLOSURE 1 R 2aIsopropenylmercapto 3oz N Ac-aminoazetidin-4-ones of the formula O=C-NR2tar A =-Nit "s-o CHs wherein R reprsents a hydrogen atom or a formylgroup and Ac represents the acyl radical of an organic acid, showantibacterial properties, but are primarily useful as intermediates.

SUMMARY OF THE INVENTION The present invention relates toalkenylmercapto compounds, especially to 1-R-2a-isopropenylmercapto-3a-N- Ac-amino-azetidin-3-ones of the formulawherein R represents a hydrogen atom or a formyl group and Ac representsthe acyl radical of an organic acid.

These compounds are useful as antibacterial substances,

but above all as intermediates in the preparation of pharmacologicallyuseful substances, especially those having the structure of7-aminocephalosporanic acid.

DESCRIPTION OF THE PREFERRED EMBODIMENTS A group Ac primarily representsthe acyl radical of an organic carboxylic acid, especially the acylradical of an optionally substituted aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic orheterocyclic-aliphatic carboxylic acid, as well as the acyl radical of acarbonic acid semi-derivative.

The aliphatic radical of an aliphatic carboxylic acid, which term alsoincludes formic acid, is an optionally substituted aliphatic hydrocarbonradical, such as an alkyl, alkenyl or alkinyl radical, especially alower alkyl or lower alkenyl radical, as well as also a lower alkynylradical, which can, for example, contain up to 7, preferably up to 4,carbon atoms. Such radicals can optionally be monosubstituted,disubstituted or polysubstituted by functional groups, for example, byfree, etherified or esterified hydroxyl or mercapto groups, such aslower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionallysubstituted phenyloxy or phenyl-lower alkoxy, lower alkylmercapto oroptionally substituted phenylmercapto or phenyl-lower alkylmercapto,lower alkoxycarbonyloxy or lower alkanoyloxy groups, as well as halogenatoms, and furthermore by nitro groups, optionally substituted aminogroups, acyl, such as lower alkanoyl groups, or optionally functionallymodified carboxyl groups, such as carbo-lower alkoxy, optionallyN-substituted carbamoyl or cyano groups.

3,703,512 Patented Nov. 21, 1972 A cycloaliphatic orcycloaliphatic-aliphatic radical of a corresponding carboxylic acid isan optionally substituted cycloaliphatic or cycloaliphatic-aliphatichydrocarbon radical, for example, a monocyclic, bicyclic or polycycliccycloalkyl or cycloalkenyl group or cycloalkylor cycloalkenyl-loweralkyl or -lower alkenyl group, wherein a cycloalkyl radical, forexample, contains up to 12, such as 3-8, preferably 3-6, ring carbonatoms, whilst a cycloalkenyl radical can, for example, contain up to 12,such as 3-8, especially 5-8, preferably 5 or 6, ring carbon atoms, aswell as l to 2 double bonds and the aliphatic part of acycloaliphatic-aliphatic radical can, for example, contain up to 7,preferably up to 4, carbon atoms. The above cycloaliphatic orcycloaliphatic-aliphatic radicals can, if desired, be monosubstituted,disubstituted or polysubstituted, for example, by optionally substitutedaliphatic hydrocarbon radicals, such as, for example, the optionallysubstituted lower alkyl groups mentioned above, or, for example, likethe abovementioned aliphatic hydrocarbon radicals, by functional groups.

The aromatic radical of a corresponding carboxylic acid is an optionallysubstituted aromatic hydrocarbon radical, for example, a monocyclic,bicyclic or polycyclic aromatic hydrocarbon radical, especially a phenylradical, as well as a biphenylyl or naphthyl radical, which canoptionally be monosubstituted, disubstituted or polysubstituted, forexample, like the abovementioned aliphatic and cycloaliphatichydrocarbon radical.

The araliphatic radical in an araliphatic carboxylic acid is, forexample, an optionally substituted araliphatic hydrocarbon radical, suchas an optionally substituted aliphatic hydrocarbon radical which, forexample, possesses up to 3 optionally substituted monocyclic, bicyclicor polycyclic aromatic hydrocarbon radicals, and primarily represents aphenyl-lower alkyl or phenyl-lower alkenyl as well as phenyl-loweralkynyl radical, such radicals containing, for example, 1-3 phenylgroups and optionally being monosubstituted, disubstituted orpolysubstituted in the aromatic and/or aliphatic portion, for example,like the above-mentioned aliphatic and cycloaliphatic radicals.

Heterocyclic radicals in heterocyclic or heterocyclicaliphaticcarboxylic acids are especially monocyclic, as well as bicyclic orpolycyclic, azacyclic, thiacyclic, oxacyclic, thiazacyclic, oxazacyclicor diazacyclic radicals of aromatic character which can optionally bemonosubstituted, disubstituted or polysubstituted, for example, like theabove-mentioned cycloaliphatic radicals. The aliphatic portion inheterocyclic-aliphatic radicals has, for example, the significance givenfor the corresponding cycloaliphatic-aliphatic or araliphatic radicals.

The acyl radical of a carbonic acid semi-derivative is preferably theacyl radical of a corresponding half-ester, wherein the esterifyingorganic radical represents an optionally substituted aliphatic,cycloaliphatic, aromatic or araliphatic hydrocarbon radical or aheterocyclic-aliphatic radical, primarily the acyl radical of a loweralkyl halfester of carbonic acid which is optionally substituted,preferably in the a-position, as well in the fi-Position (that is to saya carbo-lower alkoxy radical which is optionally substituted in thelower alkyl portion, preferably in the w, as well as in thefit-position), as well as a lower alkenyl, cycloalkyl, phenyl orphenyl-lower ialkyl half-ester of carbonic acid which is optionallysubstituted in the lower alkenyl, cycloalkyl, phenyl or phenyl-loweralkyl portion, respectively (that is to say a carbo-lower alkenyloxy,carbo-cycloalkoxy, carbo-phenyloxy or carbo-phenyllower alkoxy radicalwhich is optionally substituted in the lower alkenyl, cycloalkyl, phenylor phenyl-lower alkyl portion, respectively). Acyl radicals of acarbonic acid half-ester are furthermore corresponding radicals of loweralkyl half-esters of carbonic acid, in which the lower alkyl portioncontains a heterocyclic group, for example, one of the abovementionedheterocyclic groups of aromatic character, the lower alkyl radical andthe heterocyclic group being optionally substituted. Such acyl radicalsare carbolower alkoxy groups which are optionally substituted in thelower alkyl portion and which contain an optionally substitutedheterocyclic group of aromatic character in the lower alkyl radical.

A lower alkyl radical is, for example, a methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec.-butyl or tert.- butyl, as well asn-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl group, while a loweralkenyl radical can, for example, be a vinyl, allyl, isopropenyl, 2- or3-methallyl or 3-butenyl group, and a lower alkynyl radical, forexample, a propargyl or Z-butynyl group.

A cycloalkyl group is, for example, a cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl, as well as adamantyl group, anda cycloalkenyl group is, for example, a 2- or 3-cyclopentenyl, 1-, 2- or3-cyclohexenyl or 3- cycloheptenyl, as well as a 2-cyclopropenyl group.A cyclo alkyl-lower alkyl or -lower alkenyl radical is, for example, acyclopropyl-, cyclopentyl-, cyclohexylor cycloheptylmethyl, -l,1-ethylor -l,2-ethyl, -l,1-propyl, -1,2-propyl or -1,3-propyl, -vinyl or -allylgroup, while a cycloalkenyllower alkyl or -lower alkenyl grouprepresents, for example, a 1-, 2- or 3-cyclopentenyl-, 1-, 2- or3-cyclohexenylor 1-, 2- or 3-cycloheptenyl-methyl, -l,l-ethyl or 1,2-ethyl, -l,l-propyl, -l,2-propyl or -l,3-propyl, -vinyl or -allyl group.

A naphthyl radical is a lor Z-naphthyl radical, while a biphenylyl grouprepresents, for example, a 4-biphenylyl radical.

A phenyl-lower alkyl or phenyl-lower alkenyl radical is, for example, abenzyl, 1- or 2-phenylethyl, 1-, 2- or 3- phenylpropyl, diphenylmethyl,trityl, 1- or 2-naphthylmethyl, styryl or cinnamyl radical.

Heterocyclic radicals are, for example, monocyclic monoazacyclic,monothiacyclie or monooxyacyclic radicals of aromatic character, such aspyridyl, for example, 2-pyridyl, 3-pyridyl or 4-pyridyl radicals,thienyl, for example, 2-thienyl radicals, or furyl, for example, 2-furylradicals, or bicyclic monoazacyclic radicals of aromatic character, suchas quinolinyl, for example, 2-quinolinyl or 4-quinolinyl radicals, orisoquinolinyl, for example, 1- isoquinolinyl radicals, or monocyclicthiazacyclic or oxazacyclic as well as diazacyclic radicals of aromaticcharacter, such as oxazolyl, isoxazolyl, thiazolyl or isothiazolyl, aswell as pyrimidinyl radicals. Heterocyclic-aliphatic radicals are loweralkyl or lower alkenyl radicals containing heterocyclic radicals,especially those mentioned above.

By etherified hydroxyl groups there are primarily to be understood loweralkoxy, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy,n-butyloxy, isobutyloxy, sec.-butyloxy, tert.-butyloxy, n-pentyloxy ortert.-pentyloxy groups, as well as substituted lower alkoxy, such ashalogeno-lower alkoxy, especially 2-halogeno-lower alkoxy, for example,2,2,2-trichloroethoxy or 2-iodoethoxy groups, furthermore loweralkenyloxy, for example, vinyloxy or allyloxy groups, loweralkenylenedioxy, for example, methylenedioxy or ethylenedioxy, as wellas isopropylidenedioxy groups, cycloalkoxy, for example, cyclopentyloxy,cyclohexyloxy or adamantyloxy, groups, phenyloxy groups, phenyl-loweralkoxy, for example, benzyloxy or 1- or Z-phenylethoxy groups, or loweralkoxy groups substituted by monocyclic monoazacyclic, monooxacyclic ormonothiacyclic groups of aromatic character, such as pyridyl-loweralkoxy, for example, 2-pyridylmethoxy groups, furyl-lower alkoxy, forexample, furfuryloxy groups, or thienyl-lower alkoxy, for example, 2-thienyloxy groups.

As etherified mercapto groups, lower alkyl mercapto, for example,methylmercapto or ethylmercapto grOupS, phenylmercapto groups, orphenyl-lower alkylrnercapto,

for example, benzylmercapto groups may be mentioned.

Esterified hydroxyl groups are primarily halogen, for example, fluorine,chlorine, bromine or iodine atoms, as well as lower alkanoyloxy, forexample, acetyloxy or propionyloxy groups.

Substituted amino groups are monosubstituted or disubstituted aminogroups, in which the substituents primarily represent optionallysubstituted monoor divalent aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals,as well as acyl groups. Such amino groups are especially loweralkylamino or dilower alkylamino groups, for example, methylamino,ethylamino, dimethylamino or diethylamino groups, or lower alkyleneaminogroups, which are optionally interrupted by hetero-atoms, such as oxygenor sulfur atoms or nitrogen atoms which are optionally substituted, forexample, by lower alkyl groups, such as pyrrolidino, piperidino,morpholino, thiomorpholino or 4-methyl-piperazino groups, as well asacylamino groups, especially lower alkanoylamino groups, such asacetylamino or propionylamino groups.

Lower alkanoyl is e.g. acetyl or propionyl.

A carbo-lower alkoxy radical is, for example, a carbomethoxy,carbethoxy, carbo-n-propyloxy, carbo-isopropyloxy, carbo-tert.-butyloxyor carbo-tert.-pentyloxy group.

Optionally N-substituted carbamoyl groups are, for example, N-loweralkyl-carbamoyl or N,N-di-lower alkylcarbamoyl groups, such asN-methyl-, N-ethyl-, N,N-dimethylor N,N-diethyl-carbamoyl groups.

A carbo-lower alkenyl radical is, for example, the carbovinyloxy group,while carbo-cycloalkoxy and carbophenyl-lower alkoxy groups, in whichthe cycloalkyl or phenyl-lower alkyl radical have the abovementionedsignificance, represent, for example, carbo-adamantyloxy,carbo-benzyloxy or carbo-diphenylmethoxy, as well ascarbo-(a-4-biphenylyl-a-methylethoxy) groups. Carbolower alkoxy groupsin which the lower alkyl radical contains, for example, a monocyclicmonoazacyclic, monooxacyclic or monothiacyclic group are, for example,carbofuryl-lower alkoxy, such as carbo-furfuryloxy groups, orcarbo-thienyl-lower alkoxy, such as carbo-Z-thienyloxy groups.

The compounds of the above type may be present in the form of mixturesof isomers or as pure isomers.

Compounds of Formula I show valuable pharmacological properties;particularly, they are active against grampositive bacteria, such asStaphylococcus aureus, in dilutions of up to 0.01% and are, therefore,useful as antibacterial substances. They serve primarily asintermediates for the manufacture of valuable, for example,pharmacologically active compounds.

Particularly valuable compounds are those of formula wherein Ac' denotesan acyl residue occurring in pharmacologically active N-acyl derivativesof 6-amino-penicillanic acid or of 7-amino-cephalosporanic acid, suchas, for example, the residue of formula wherein m represents an integerfrom 0 to 4, preferably 1, and a carbon atom of a preferably unbranchedalkylene radical of formula -(C Hzm) can optionally be sub stituted byan optionally substituted amino group, a free, etherified or esterifiedhydroxyl or mercapto group or a free or functionally modified carboxylgroup, for example, by one of the abovementioned groups of this kind,and wherein Y stands for an aromatic or cycloaliphatic hydrocarbonradical or heterocyclic radical, the latter preferably of aromaticcharacter, optionally substituted in the nucleus, for example, by thesubstituents of the above alkylene radical, as well as by sulfo or nitrogroups, or for a hydroxyl or mercapto group which is etherificd by anaromatic or cycloaliphatic hydrocarbon radical or by a heterocyclicradical, the latter preferably of aromatic character, for example, a2,6-dimethoxybenzoyl, tetrahydronaphthoyl, 2-methoxy-naphthoyl,2-ethoxy-naphthoy1, phenylacetyl, phenyloxyacetyl, phenylthioacetyl,bromophenylthioacetyl, 2 phenyloxypropionyl, a phenyloxyphenylacetyl,a-methoxy-phenylacetyl, a-methoxy-3,4-dichlorophenylacetyl,a-cyano-phenylacetyl, phenylglycyl (optionally having a protected aminogroup), benzyloxycarbonyl, benzylthioacetyl, benzylthiopropionyl,hexahydrobenzyloxycarbonyl, cyclopentanoyl, a-amino-cyclopentanoyl ora-amino-cyclohexanoyl (optionally having a protected amino group),Z-thienylacetyl, a-cyano-2-thienylacetyl, a-amino-2-thienylacetyl(optionally having a protected amino group), 3-thienylacetyl,2-furylacetyl, 2 phenyl methylisoxazolyl-carbonyl or2-(2-chlorophenyl)-5-methyl-isoxazolylcarbonyl group, or represents aradical of one of the formulae C H CO- and C H CO, wherein n representsan integer up to 7, and the chain can be straight or branched andoptionally interrupted by an oxygen or sulfur atom and/or substituted,for example, by halogen atoms, trifluoromethyl, free or functionallymodified carboxyl, such as cyano, free or substituted amino, as well asnitro groups, for example, a propionyl, butyryl, hexanoyl, octanoyl,butylthio-acetyl, acrylyl, crotonyl, 2-pentenoyl, allylthio-acetyl,chloroacetyl, 3-chloropropionyl, 3-bromopropionyl, aminoacetyl,Z-carboxypropionyl, cyanoacetyl or 2-cyano-3- dimethyl-acrylyl group, orrepresents a radical of the formula Z-NH--CO-, wherein Z denotes anaromatic or aliphatic hydrocarbon radical which is optionallysubistituted, especially a lower alkyl radical substituted by loweralkoxy groups and/or halogen atoms, and primarily a monocyclicarylacetyl or aryloxyacetyl or a lower alkanoyl or alkenoyl radical,e.g. phenylacetyl, 4-hydroxyphenylacetyl, phenyloxyacetyl, hexanoyl,heptanoyl or 2- hexenoyl radical, or represents an easily removable acylradical, especially the radical of a half-ester of carbonic acid, suchas a carbo-lower alkoxy, for example, carbotert.-butyloxy orcarbo-tert.-pentyloxy radical, a carbocycloalkoxy, for example,carbo-adamantyloxy radical, a carbo-phenyl-lower alkoxy, for example,carbo-diphenylmethoxy radical, or a carbo-furyl-lower alkoxy, forexample, carbo-furfuryloxy radical.

The compounds of Formula I are obtained, when a 1 R Zoe-(Z-Rcarbonyloxy-2-propylmercapto)-3u-N- Ac aminoazetidin-4-one compound ofthe formula CH: (II) wherein R represents an organic residue, isdecomposed thermally, and, if desired, in a resulting compound a formylgroup R is split off, and/or, if desired, in a resulting compound havingan acyl residue possessing protected functional groups, these groups areliberated and/or, if desired, a resulting isomer mixture is resolvedinto the individual isomers.

An organic residue R is, for example, one of the abovementionedoptionally substituted hydrocarbon residues, primarily an optionallysubstituted aliphatic or aromatic hydrocarbon residue, such as one ofthe above mentioned corresponding residues, especially a lower alkyl,such as a methyl residue, or a monocyclic aromatic hydrocarbon,especially an optionally substituted phenyl residue, for example, asmentioned above.

The thermal decomposition of the starting material is preferablyperformed in the presence of an inert solvent or solvent mixture,especially a suitable hydrocarbon, such as an aliphatic or aromatichydrocarbon, for

example, high-boiling petroleum ether, benzene, toluene or xylene, attemperatures of about 50 C. to about 150 C., preferably from about 70 C.to about C., if desired in an inert gas, such as a nitrogen atmosphere.

In a resulting compound of the Formula I, in which R represents theformyl residue, the latter can be replaced by hydrogen by hydrolysis,alcoholysis, ammonolysis or amiuolysis, as well as by treatment with aspecific decarbonylation reagent. Hydrolysis can, for example, beperformed in an aqueous medium by treatment with a suitable inorganicbase, such as an alkali metal or alkaline earth metal hydroxide orcarbonate, for example, sodium, potassium, calcium or barium hydroxideor carbonate, as well as an alkali metal hydrogen carbonate, forexample, sodium or potassium hydrogen carbonate. The alcoholysis withalcohols, such as lower alkanols, for example, methanol or ethanol, aswell as with mercaptans, is preferably carried out in the presence ofappropriate alcoholates or thiolates, such as alkali metal loweralkanolates, for example, sodium methylate or ethylate, as well as ofWeakly basic acylates, such as alkali metal lower alkanoates, forexample, sodium acetate.

The ammonolysis with ammonia, as Well as with quaternary ammoniumhydroxides, for example, benzyltrimethylammonium hydroxide ortetrabutylammonium hydroxide, also leads to the removal of a formylgroup R When using ammonia the process is, for example, carried out in atwo-phase system; the ammonia, which is preferably used in the form ofan aqueous solution, passes then into the organic phase at a lowconcentration and eifects the splitting-oh of the formyl group.Aminolysis can be carried out with amines, especially primary orsecondary, primarily aliphatic or aromatic, amines, for example,ethylamine, diethylamine, pyrrolidine or aniline.

Specific decarbonylation reagents are, for example, complex transitionmetal compounds which can form a stable complex together with carbonmonoxide, such as tri-substituted tris-phosphine-rhodium halides, forexample, tris-(triphenyl)-phosphine-rhodium chloride. They arepreferably used in a suitable inert solvent, for example, benzene, or asolvent mixture, if desired, in an inert gas, for example, nitrogenatmosphere.

The removal of the formyl group, which, for example, when using adecarbonylation reagent is preferably carried out at an elevatedtemperature, can be directly carried out on the starting material ofFormula II; under these reaction conditions the thermal decompositionoccurs with the formation of the isopropenyl radical and the formylgroup is simultaneously replaced by hydrogen.

The starting materials used in the above process, in which R representsa formyl group, can be obtained, when a 2-isocyanato-3,3-dimethyl-6-N-Ac-amino-4-thial-azabicyclo[3,2,0]heptan-7-one of the formula 0 CH- C Herr Ace-NH s 3 (III) (configuration of G-amino-pencillanic acid),wherein Ac has the significance of an acyl Ac, in which free functionalgroups optionally present in the acyl residue are protected, is reactedwith a 2-halogeno-lower alkanol of formula Ro-OH, wherein R represents a2-halogenolower alkyl residue, in which halogen has an atomic weight ofabove 19, a resulting compound of the formula CHCH CH Aco-NH s 1v(configuration of 6-amino-pencillam'c acid) is treated with a chemicalreducing agent in the presence of water, and a2-hydroxy-3,3-dimethyl-6-N-Ac-amino-4-thia-lazabicyclo[3,3,0]heptan-7-one of the formula l l C CHCHAcu-NII \S/ CH: (V)

(configuration of 6-amino-penicillanic acid) is treated with anoxidising agent which confers an acyloxy group of formula -OC(=O)R and,if desired, in a resulting compound with an acyl residue havingprotected functional groups, such groups are liberated, and/or, ifdesired, a resulting isomer mixture is resolved into the individualisomers.

In the above starting material, free functional groups in the acylresidue Ac which have to be protected during the reaction, for example,in a manner which is in itself known, are primarily free hydroxyl,mercapto and amino groups, as well as carboxyl groups. The latter can,for example, be protected by conversion into an ester, for example, anester which is easily split under acid conditions, such as a methylester, which is polysubstituted by optionally substituted aliphatic oraromatic hydrocarbon residues, such as the tert.-butyl ester, or anester which is easily split by reduction, such as a Z-halogeno-loweralkyl ester, especially the 2,2,2-trichloroethyl ester, and the formercan, for example, be protected by conversion to an easily splittableacyl derivative, such as a carbo-lower alkoxy derivative, which can besplit under acid conditions, in which the lower alkyl residue in theOL'pOSltlQn is preferably branched or, for example, substituted byoptionally substituted aromatic hydrocarbon residues, for example, thecarbo-tert.-butyloxy derivative, or into a carbo-Z-halogeno-lower alkoxyderivative, which is easily split by reduction, such as acarbo-2,2,2-trichloroethoxy derivative.

The 2-halogeno-lower alkyl radical R in the starting material maycontain one, two or more halogen, i.e. chlorine, bromine or iodineatoms, with 2-chloroand 2-bromo-lower alkyl radicals containing several,preferably three chlorine and bromine atoms, respectively, whereas a2-iodo-lower alkyl radical may have only one iodine atom. The radical Respecially represents a 2- polychloro-lower alkyl, such as a2-polychloroethyl, primarily the 2,2,2-trichloroethyl, as well as2,2,2-trichloro-l-methyl-ethyl radical, but can also, for example,denote a 2-polybromo-lower alkyl, such as 2,2,2-tribro moethyl, or a2-iodo-lower alkyl radical, for example, the Z-iodoethyl radical.

The reaction of a compound of the Formula III with a suitable2-halogeno-lower alkanol, especially a 2-halo- .genoethanol, forexample, with 2,2,2-trichloroethanol, is optionally carried out in aninert solvent, for example, in a halogenated hydrocarbon, such as carbontetrachloride, chloroform or methylene chloride or in an aromaticsolvent, such as benzene, toluene or chlorobenzene, preferably withwarming.

In this reaction it is possible to start from precursors of compounds ofthe Formula III, form the latter under the reaction conditions and thusto obtain the desired starting material directly. If, for example, anappropriate 3,3-dimethyl-6-N-Ac -amino-7-oxo-4-thia l aza-Z-bicyclo[3.2.0]heptane-carboxylic acid azide (configuration of6-amino-penicillanic acid), which can, for example, be obtained byconverting a 3,3-dimethyl-6N-Ac amino-7-oxo-4-thia l aza 2bicyclo[3.2.0]heptanecarboxylic acid (configuration of6-amino-penicillanic acid), for example, a 6-N-Ac -amino-penicillanicacid, or a suitable salt, especially an ammonium salt thereof, into amixed anhydride (for example, by treatment with a halogenoformic acidlower alkyl ester, such as chloroformic acid ethyl ester, in thepresence of a basic reagent, such as triethylamine) and treating thelatter with a metal azide, such as sodium azide, or an ammonium azide,for example, benzyltrimethylammonium azide, is used, this azide, in theabsence or presence of the 2-halogeno-lower alkanol, decomposes with theevolution of nitrogen under the reaction conditions, for example, onwarming, to give the desired isocyanato compound of the Formula HI,which usually does not have to be isolated and which in the presence ofthe Z-halogeno-lower alkanol is directly converted to the desiredstarting material.

In a compound resulting from the above procedure the chlorine or bromineatom in a 2-monochloroand 2- monbromo-lower alkyl radical, respectively,may be exchanged for an iodine atom, for example, by treatment with asuitable iodine salt, such as an alkali metal iodide, e.g. potassiumiodide, in the presence of a suitable solvent, e.g. acetone.

In a resulting intermediate an acyl radical, especially the acyl radicalof a suitable half-ester of carbonic acid, such as a carbo-lower alkoxyradical which can be split under acid conditions, for example, thecarbo-tert.-butyloxy, as well as carbo-tert.-pentyloxy,carbo-adamantyloxy or carbodiphenylmethoxy radical, for example, bytreatment with trifiuoracetic acid.

In a resulting intermediate with a free amino group the latter can beacylated according to methods which are in themselves known, forexample, like a free hydroxyl group in the manner described below, i.e.by treatment with a free carboxylic acid or especially a reactivefunctionally modified carboxylic acid, for example, with an acidchloride or acid anhydride, optionally in the presence of a suitablecondensing reagent.

The treatment of an intermediate of the Formula IV with the chemicalreducing agent is carried out under mild conditions, in most cases atroom temperature or even with cooling. At least one mole, usually anexcess of water is present.

Chemical reducing agents are primarily suitable reducing metals, as wellas reducing metal compounds, e.g. metal alloys or metal amalgams, asWell as strongly reducing metal salts. Particularly useful are zinc,zinc alloys, e.g. zinc-copper or zinc amalgam, furthermore magnesium,which reagents are advantageously used in the presence ofhydrogen-furnishing compounds capable of producing nascent hydrogentogether with the metals, metal alloys and metal amalgams, zinc, forexample, in the presnce of acids, such as organic carboxylic, e.g. loweralkane carboxylic acids, above all acetic acid, with the addition ofwater, as Well as in the presence of aqueous alcohols, such as loweralkanols, e.g. methanol, ethanol or isopropanol, which may be usedtogether with an organic carboxylic acid, and alkali metal amalgams,such as sodium or potassium amalgam, as well as aluminum amalgam in thepresence of moist solvents, such as others or lower alkanols. Stronglyreducing metal salts are primarily chromium-II compounds, for example,chromium-II-chloride or chromium-II-acetate, which are used in thepresence of aqueous media, containing organic solvents miscible withWater, such as lower alkanols, lower alkanecarboxylic acids or ethers,for example, methanol, ethanol, acetic acid, tetrahydrofuran, dioxane,ethylene glycol dimethyl ether or diethylene glycol dimethyl ether.

Oxidizing reagents, furnishing acyloxy groups of the formula -OC(==O)-Rare preferably oxidizing heavy metal carboxylates, preferablylead-IV-carboxylates, such as lead-IV-alkylcarboxylates, especiallylead- IV-lower alkylcarboxylates and primarily lead-tetraacetate, asolead tetrapropionate or lead tetrastearate, as well as optionallysubstituted lead tetrabenzoates, for example, lead tetrabenzoate or leadtetra-3-bromobenzoate, also thallium-III-carboxylates, for example,thallium-III-acetate, or mercury-II-carboxylates, such asmercury-II-acetate. If desired, these oxidizing agents can be formed insitu, for example, by reacting lead dioxide or mercuryII-oxide with anorganic carboxylic acid, such as acetic acid. At least an equivalentamount of the oxidizing reagent is used; normally an excess thereof isemployed.

The above heavy metal carboxylates, especially the corresponding lead-IVcompounds, are advantageously used in the presence of a source of light,the process preferably being carried out under ultra-violet light, aswell as light of longer wavelengths, such as visible light, optionallywith the addition of suitable sensitisers. Ultra- 'violet light haspreferably a main wavelength range of above 280 111,44, primarily ofabout 300 mg to about 350 m this can, for example, be achieved bysuitably filtering the ultra-violet light through an appropriate filter,for example, a glass filter, or through suitable solutions, such as saltsolutions, or other liquids which absorb light of shorter wavelengths,such as benzene or toluene. The ultraviolet light is preferablygenerated by means of a high pressure mercury vapour lamp.

The above reaction can, for example, be carried out by treating anintermediate of the Formula IV with the necessary quantity, usually anexcess of the oxidizing agent capable of furnishing an acyloxy group ofthe Formula -OC(=O)R usually in the presence of a suitable diluent, suchas benzene, acetonitrile or acetic acid, if necessary, while cooling orwarming and/or in an inert gas atmosphere, while irradiating 'with'ultraviolet light.

In a resulting starting material of the Formula II, protected functionalgroups in an acyl residue Ac can, in a manner which is in itself known,be converted into the corresponding free groups. Thus, a suitable acylresidue, such as a carbo-lower alkoxy residue which can be split underacid conditions, for example, the carbo-tert.- butyloxy, as Well ascarbo-tert.-pentyloxy, carbo-adamantyloxy or carbo-diphenylmethoxyresidue, or a carbo- 2-halogeno-lower alkoxy residue which can be splitby reduction, for example, the carbo-Z,2,2-trichloroethoxy residue, canbe split off, the latter, for example, by treatment with one of theabove-mentioned chemical reducing agents, particularly zinc, in thepresence of aqeuous acetic acid, and the former, for example, bytreatment with trifluoroacetic acid.

Starting materials of the Formula II, in which R represents a hydrogenatom, can be obtained, when a 2-hydroxy 3,3 dimethyl 6 N Ac amino 4thia- 1 azabicyclo[3.2.0]heptan 7 one compound of the Formula V istreated with a hydride reducing agent which is inert towards amidegroupings, the hydroxyl group in a resulting 2a (2 hydroxymethyl 2propylmercapto) 3a N Ac amino azetidin 4 one compound of the formula isoptionally esterified, and a compound of the Formula VI or an O-ester,especially an O-ester with an orgamc carboxylic acid, as well as acarbonic acid semi-deriva- 10 tive, thereof is treated with an oxidisingagent furnishing an acyloxy group of the formula -OC(=O)-R and, ifdesired, in a resulting compound with an acyl residue having protectedfunctional groups, such groups are liberated, and/or, if desired, aresulting isomer mixture is resolved into the individual isomers.

Hydride reducing reagents which do not reduce an amide grouping areprimarily hydrides containing boron, such as, for example, diborane andespecially alkali metal or alkaline earth metal borohydrides, above allsodium boro hydride. Complex organic aluminum hydrides, such as alkalimetal tri-lower alkoxy-aluminum hydrides, for example,lithium-tri-tert.-butyloxy-aluminum hydride, can also be used.

These reducing agents are preferably used .in the presence of suitablesolvents or mixtures thereof, alkali metal borohydride, for example, inthe presence of solvents possessing hydroxyl or ether groupings, such aslower alkanols, for example, methanol or ethanol, as Well asisopropanol, furthermore tetrahydrofuran or diethylene glycol dimethylether, with cooling or warming, if necessary.

If desired, the hydroxyl group in a compound obtainable in accordancewith the process can be acylated in a manner which is in itself known.The usual acylating agents, such as acids or their reactive derivativesare used for this purpose, the former, for example, in the presence of asuitable condensation agent, such as a carbodiimide, for example,dicyclohexylcarbodiimide, and the latter, if necessary, in the presenceof a basic reagent, such as an organic tertiary base, for example,triethylamine or pyridine. Reactive derivatives of acids are anhydrides,including internal anhydrides, such as ketenes, isocyanates orisothiocyanates, or mixed anhydrides, especially anhydrides which can bemanufactured with halogenoformic acid esters, for example, chloroformicacid ethyl ester, and furthermore halides, primarily chlorides, orreactive esters, such as esters of acids with alcohols or phenolscontaining electron-attracting groupings, as well as with N-hydroxycompounds, for example, cyanomethanol, pnitrophenol orN-hydroxy-succinimide. The acylation reaction can be performed in thepresence or absence of solvents or solvent mixtures, if necessary, withcooling or warming, in a closed vessel under pressure and/or in an inertgas atmosphere, for example, nitrogen atmosphere. Esters with inorganicacids, especially hydrohalic acids, can, for example, be obtained bytreatment with the usual halogenating agents, such as halides ofphosphorus and of sulphur, for example, thionyl chloride or phosphorusoxychloride.

O-esters of intermediates of the Formula VI are primarily those withorganic carboxylic acids, such as the above mentioned optionallysubstituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylicacids, as well as with semi-derivatives of carbonic acid, also thosewith organic sulfonic acids, as well as with inorganic acids such ashydrohalic acids, for example, hydrogen chloride or hydrogen bromide.

As oxidising agents furnishing acyloxy groups of the formula -OC(=O)-Rthe above mentioned oxidising heavy metal carboxylates, especiallylead-IV-alkanoates and preferably lead-tetraacetate should primarily bementioned, with the process being advantageously carried out as outlinedin the presence of a light source, primarily a source of ultravioletlight, and in the persence of a suitable solvent or diluent.

In a resulting starting material of the Formula II, when desired,protected functional groups in an acyloxy group Ac may, as describedabove, be converted into the free groups.

As has been mentioned, the resulting compounds of the Formula I canserve as intermediate products for the manufacture of valuable, forexample, pharmacologically active compounds or compounds which can beused as 11 starting materials. Thus, they can, for example, be convertedinto compounds of the formula XBH-li CH: R-Nfr "s- H H: (VII) especiallyof the formula JH- i1 CH: lav-Nix "s- H H: (VIIa) wherein R represents ahydrogen atom or the acyl group Ac, and R' represents a hydrogen atom oran acyl group Ac, and wherein R represents a hydrogen atom or the acylresidue Ac of an organic carboxylic acid, especially of one of the abovementioned optionally substituted aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic orheterocyclic-aliphatic carboxylic acids, as well as the acyl residueof acarbonic acid half-derivative, and R3 represents a hydrogen atom or theacyl radical Ac of a lower alkanecarboxylic acid, including formic acid.

Compounds of the above nature, especially those in which R and R or R'and R represent acryl groups, show valuable pharmacological properties;in particular, they are active against gram-positive bacteria, such asStaphylococcus aureus in dilutions ranging to 0.01% and are, therefore,useful accordingly. They can also serve as intermediate products, suchas for the manufacture of valuable compounds, for example,pharmacologically active compounds.

They can be obtained, when the isopropenyl group is saturated incompounds of Formula I and, if desired, in a resulting compound theformyl group is split off and/or, if desired, in a resulting compoundthe nitrogen atom of the lactam grouping carrying the hydrogen atom isacylated and/ or, if desired, in a resulting compound an acylaminogrouping is split and, if desired, the liberated amino group is acylatedand/or, if desired, in a resulting compound having an acyl radical withprotected functional groups these groups are liberated and/or, ifdesired, a resulting isomer mixture is resolved into the individualisomers.

The reduction of the isopropenyl radical in the compounds of Formula Iis preferably performed by treatment with catalytically activatedhydrogen, for example, with hydrogen in the presence of a noble metalcatalyst which, for example, contains palladium or platinum, ifnecessary, at elevated pressure and/or with heating.

A formyl group R can be replaced by hydrogen, and the latter by an acylresidue, for example, according to the decarbonylation and acylationmethods described above, the latter preferably at an elevatedtemperature, while in a resulting compound it is possible, if desired,to split a suitable acylamino grouping in the manner mentioned above,and, if desired, to acylate a free amino group formed in this way;protected functional groups can be liberated, for example, as mentionedabove.

Compounds of Formula I, primarily those in which Ac represents an acylradical Ac which is easily removable, especially under acid conditions,such as a suitable acyl radical of a carbonic acid half-ester, such as acarbolower alkoxy radical, which is optionally substituted in the loweralkyl portion, preferably in the OL-POSltlOIl, as well as a carbo-loweralkenyloxy, carbo-cycloalkoxy, carbo-phenyloxy or carbo-phenyl-loweralkoxy radical which is optionally substituted in the lower alkenyl,cycloalkyl, phenyl and phenyl-lower alkyl portion, respectively, or acarbo-lower alkoxy radical having a heterocyclic group of aromaticcharacter in the lower alkyl portion, preferably in the a-position, andR denotes a hydrogen atom, can furthermore be converted to compounds ofthe formula especially to those compounds, in which R has thesignificance of R; compounds of this type are known, for example, asvaluable intermediate products in the synthetic manufacture of7-acylamino-cephalosporanic acid compounds; see, for example, AustrianPatents Nos. 263,768 and 264,537.

They are obtained, when compounds of Formula VII, wherein Ac preferablyrepresents one of the abovementioned easily removable radicals Ac aretreated with a strong oxygen-containing acid, and, if desired, in aresulting compound of Formula IX having an unsubstituted nitrogen atomin the 3-position, the latter is acylated.

The ring closure can be elfected by treatment with a strong inorganic ororganic oxygen-containing acid, such as organic carboxylic or sulfonicacids, especially a strong lower alkanecarboxylic acid, which isoptionally substituted by hetero-radicals, preferably by halogen atoms,such as an a-halogeno-acetic or a-halogenopropionic acid, whereinhalogen preferably denotes fluorine, as well as chlorine, primarilytrifluoroacetic acid. The reaction is carried out in the absence orpresence of an inert solvent, such as dioxane, or of a mixture ofdiluents and, if necessary, with cooling, for example, at temperaturesof about -30 to about +10 C., and/or in an inert gas, for example,nitrogen atmosphere.

Acylation of a hydrogen-containing nitrogen atom in a resulting compoundcan, for example, be carried out as described above, if desired, instages.

Mixtures of isomers obtainable according to the above processes can beresolved into the individual isomers according to methods which are inthemselves known, for example, by fractional crystallization, adsorptionchromatography (column or thin layer chromatography) or other suitableresolution processes. Resulting racemates having salt-forming groups,into which, in view of the racemate resolution, suitable substituentscan temporarily be introduced in the usual manner, can be resolved intothe antipodes in the usual manner, for example, by forming a mixture ofdiastereo-isomeric salts with optically active salt-forming reagents,resolving the mixture into the diastereoisomeric salts and convertingthe separated salts into the free compounds, or by fractionalcrystallization from optically active solvents.

The above processes also comprises those modifications according towhich compounds formed as intermediates are used as starting materialsand the remaining process stages are carried out with these or theprocess is interrupted at any stage; furthermore, starting materials canbe used in the form of derivatives, for example, of salts, or can beformed during the reaction.

The invention also comprises new intermediate products, as well asprocesses for their manufacture.

Preferably, those starting materials are used and the reactionconditions are so chosen that the compounds mentioned above as beingpreferred are obtained.

The compounds of the present invention having pharmacological effectcan, for example, be used in the form of pharmaceutical preparations inwhich they are in admixture with a solid or liquid pharmaceuticalexcipient and which are suitable for enteral or parenteraladministration. Suitable excipients, which are inert towards the activesubstances, are, for example, water, gelatine, saccharides, such aslactose, glucose or sucrose, starches,

such as corn starch, wheat starch or arrowroot, stearic acid or saltsthereof, such as magnesium or calcium stearate, talc, vegetable fats andoils, alginic acid, benzyl alcohols, glycols or other known excipients.The preparations may be in solid form, for example, as tablets, drages,capsules or suppositories, or in a liquid form, for example, assolutions, suspensions or emulsions. They can be sterilized and/orcontain auxiliary substances such as preservatives, stabilizers, wettingagents or emulsifiers, solubilizing agents, salts for regulating theosmotic pressure and/or buifers. They can, furthermore, contain otherpharmacologically usable substances. The pharmaceutical preparations,which are also comprised by the present invention, can be formulated ina manner which is in itself known.

The invention is described in the following examples; temperatures aregiven in degrees centigrade.

Example 1 A mixture of 0.12 g. of 1-formyl-2a-(Z-acetyloxy-Z-propyl-mercapto)-3ot-(N-phenyloxy acetyl amino)-azetidin-4-one in 12 ml.of anhydrous benzene is heated for 6 /2 hours to 80 and is thenevaporated under reduced pressure. The 1-formyl-2u-isopropenylmercapto3a (N- phenyloxyacetyl-amino)-azetidin-4-one of the formula is obtainedas a slightly yellowish, oily product which can be purified bychromatography on acid-washed silica gel and elution with a 9:1-mixtureof benzene and ethyl acetate. The amorphous product shows the followingcharacteristic bands in the infra-red absorption spectrum (in methylenechloride) 3.05p, 5.56 5.88 6.28 4, 6.72 1.

and 7.6 8

Example 2 A mixture of 0.075 g. of I-formyl-Za-(2-acetyloxy-2-propyl-mercapto)-3a- (N phenylacetyl amino)-azetidin- 4-one and 7.5 ml.of anhydrous benzene is boiled for 6 /2 hours under reflux and thenevaporated under reduced pressure. The amorphous1-formyl-2a-isopropenyl-mercapto-3 a-(N-phenylacetyl-amino)-azetidin 4one of the formula thus obtained shows characteristic bands at 3.05;,5.56 1, :90p, 6.70;]. and 7.70; in the infra-red absorption spectrum (inmethylene chloride).

Example 3 is obtained as an amorphous product which shows the followingcharacteristic bands in the infra-red spectrum (in methylene chloride):3.03m 5.55 5.85 6.69;. and 7.32M.

14 Example 4 The crude 1-formyl-2u-(2-acetyloxy 2 propyl-mercapto -3u-(N-phenyloxyacetyl-amino -azetidin-4-one, obtainable according to theprocess of Example 22, is dissolved in 50 ml. of anhydrous benzene; thesolution is kept at for 17 hours and is again evaporated to dryness.Apart from a small quantity of 1-formyl-2a-(2-acetyloxy 2propyl-mercapto) 3a (N-phenyloxyacetylamino)'azetidin-4one, the residuemainly contains 1- formyl-2a-isopropenylmercapto-3w (Nphenyloxyacetylamino)-azetidin-4-one; the crude product is furtherprocessed Without purification.

Example 5 The crude 1-formyl-2a-(2-acetyloxy-Z-propyl-mercapt0)-3a- (Nphenyloxyacetyl-amino)-azetidin-4-one resulting from the process ofExample 23 is dissolved in 50 ml. of toluene and kept for 16 hours atunder a nitrogen atmosphere and then evaporated under reduced pressure.The residue contains thel-formyl-2a-isopropenylmercapto-3a-(N-phenyloxyacetyl-amino)-azetidin-4-onewhich is further processed without purification.

Example 6 A solution of 0.741 g. of the residue resulting from theprocess of Example 24, containing l-formyl-2a-(2-benzoyloxy 2propylmercapto) 3a (N-phenyloxyacetylamino)-azetidin-4-one, in 25 ml. oftoluene is heated for 16 hours at 90 and is then cooled and diluted withbenzene. The organic solution is washed with a dilute aqueous sodiumhydrogen carbonate solution and water, dried and evaporated underreduced pressure. The l-formyl- 2a-isopropenylmercapto-3a-(Nphenyloxyacetyl-amino)- azetidin-4-one obtained as a residue is furtherprocessed without purification.

Example 7 A solution of 0.051 g. of 1-formyl-2a-(2-acetyloxy-2-propyl-mercapto) 30c (N-phenyloxyacetyl-amino)-azetidin-4-one in 3 m1.of anhydrous benzene is treated with 0.13 g. oftris-triphenyl-phosphine-rhodium chloride and boiled for 3 hours underreflux. The initially red solution changes color to brown, with a smallquantity of a precipitate forming. After cooling the precipitate isfiltered otf and the filtrate is evaporated under reduced pressure. Theresidue is chromatographed on 5 g. of acid-washed silica gel, withfractions of 5 ml. each being taken. Elution is carried out with 10 ml.of benzene, 30 ml. of a 9:1-, 25 ml. of a 4:1- and 10 ml. of a1:1-mixture of benzene and ethyl acetate and then with 25 ml. of ethylacetate. Fractions 2-6 yield a rhodium complex having a strong COabsorption at 5.1811. in the infra-red spectrum. A small quantity of1-formyl-2ot-isopropenyl-mercapto 3a (N- phenyloxyacetyl-amino)-azetidin4 one can be isolated from fractions 10-12, while from the fractions15-17 the 2ot-isopropenylmercapto-3a-(N phenyloxyacetyl-amino)-azetidin-4-one of the formula O=GNH 5 @o-cm-o-NH 'so (II) CHa isobtained as an amorphous product. The product can be obtained incrystalline form when the eluate is filtered through 0.5 g. ofacid-washed silica gel and washed out with a 1:1- mixture of benzene andethyl acetate, M.P. 156158; [a] =-70: :2 (c.=0.665 in chloroform);infra-red absorption spectrum (in methylene chloride): characteristicbands at 3.07 5.65 1, 5.96 6.29 1, 659 6.74,:1, 8.19/L, 9.25 1. and992,14.

Example 8 A solution of 0.35 g. of the crude I-formyI-Za-isopropenylmercapto 30c (N-phenyloxyacetyl-amino)- azetidin-4-one, resulting fromthe process of Example 4,

in 7.5 ml. of tetrahydrofuran, is cooled to 15, diluted with 7.5 ml. ofmethanol and treated dropwise over the course of 1 hour with 1 ml. of an0.1 N aqueous sodium hydroxide solution. The reaction mixture is stirredfor 20 minutes at 15 and is then diluted with 100 ml. of methylenechloride and washed with water; the aqueous solution is back-washed withmethylene chloride. The combined organic solutions are dried andevaporated under reduced pressure. The residue is crystallized frombenzene; the2a-isopropenylmercapto-3u-(N-phenyloxyacetylamino)-azetidin-4-one thusobtained melts at 157 158 after recrystallization from a mixture ofmethylene chloride and ether.

The residue from the mother liquors is chromatographed on 5 g. ofacid-washed silica gel; apolar byproducts are eluted with 20 ml. ofbenzene, 60 ml. of a 9: l-mixture of benzene and ethyl acetate and 50ml. of a 4:1-mixture of benzene and ethyl acetate, and a furtherquantity of the 2a-isopropenylmercapto-3a-(N-phenyloxyacetyl-amino)-azetidin-4-one is eluted with a further 50 ml. of the samemixture of benzene and ethyl acetate; strongly polar substances areeluted with ethyl acetate.

Example 9 The crude product resulting from the process of Example 5 andcontaining 1-formyl-2a-isopropenylmercapto- 3a (Nphenyloxyacetyl-amino)-azetidin-4-one, is dissolved in 45 ml. ofmethylene chloride, treated with 45 ml. of water and 0.9 ml. ofconcentrated aqueous ammonia and vigorously stirred at room temperaturefor 5 hours. The aqueous phase is washed twice with 50 ml. of methylenechloride at a time and the combined organic solutions are dried andevaporated under reduced pressure. The residue is recrystallized from amixture of methylene chloride and ether and yields the pure2a-isopropenylmercapto 3u-(N phenyloxyacetyl-amino)-azetidin-4-one, M.P.157160. The semi-crystalline mother liquor is chromatographed onacid-Washed silica gel and yields a further quantity of the desiredproduct.

Example 10 The crude 1 forrnyl-2a-isopropenylmercapto-3u-(N- carbotert.butyloxy-amino)-azetidin-4-one, obtainable resulting from the process ofExample 3, is dissolved in 10 ml. of methylene chloride, and thesolution is diluted with 10 ml. of water and treated with 10 drops ofconcentrated aqueous ammonia. The reaction mixture is vigorously stirredfor 4 hours at room temperature and is then separated into the twolayers; the aqueous phase is washed with methylene chloride and theorganic solutions are combined, dried and evaporated. The residue ischromatographed on g. of acid-washed silica gel, elution being carriedout with chloroform. Less polar byproducts are first eluted in theforerun, and then the desiredisopropenylmercapto-3u-(N-carbo-tert.-butyloxyamino)-azetidin-4-one ofthe formula is obtained, which after crystallization from cold ethermelts at 141 and after sublimation (l28132/0.001 mm. Hg) at 142-144; [a]=-26:10 (c.=0.883 in chloroform); ultra-violet absorption spectrum (inethanol): A =223 m (e=4840); infna-red absorption spectrum (in methylenechloride): characteristic bands at 3.03 1. 5.63p., 5.84;, 6.22;, 6.67.t, 7.32.,u, 7.57,u, 8.64 9.45 14 and 11.65

Example 11 A solution of 0.56 g. of the crude l-formyl-Za-isopropenyl 3a-N-phenyloxyacetyl-amino)-azetidin-4-one, resulting from the process ofExample 6, in 20 ml. of

methylene chloride is mixed with 20 ml. of water and 0.45 ml. ofconcentrated aqueous ammonia solution and the mixture is vigorouslystirred for 4 hours at room temperature. The two layers are separated;the aqueous phase is washed with methylene chloride and the combinedorganic solutions are dried and evaporated. The crystalline residue isdissolved in chloroform and filtered through 4 g. of acid-washed silicagel, whereupon an apolar yellow fraction is first obtained, followed, oneluting with chloroform, by the pure crystalline 2u-iso-propenyl-3a-(N-phenyloxyacetyl-amino)-azetidin-4-one, M.P. 157-158". The yellowfraction is chromatographed on 10 g. of acidwashed silica gel, elutionbeing carried out with chloroform; after non-polar impurities, a furtherquantity of the desired product can thus be obtained.

Example 12 Half of the crude product, obtainable according to theprocess of Example 26, containing Zoe-containing 2a-(2- acetyloxy 2propyl-mercapto) -3a-(N-phenyloxyacetylamino)-azetidin-4-one, isdissolved in 5 ml. of anhydrous dioxane and the solution is kept for 17hours at 100 and then evaporated under reduced pressure. The crudeproduct is chromatographed on 1 g. of acid-washed silica gel. Apolarby-products are eluted with 10 ml. of benzene and 20 ml. of a9:1-mixture of benzene and ethyl acetate, and the crystalline2a-isopropenylmercapto-3a-(N-phenyloxyacetyl-amide)-azetidin-4-one iseluted with 30 ml. of a 4: l-mixture of benzene and ethyl acetate, M.P.156158.

In a similar manner, 2a-isopropenylmercapto-3a-(N-carbo-tert.butyloxy-amino)-azetidin-4-one is obtained on heating 2a (2acetyloxy 2-propylmercapto)-3u-(N-carbo-tert.-butyloxy-amino)-azetidin-4one.

The starting materials used in the above examples may be prepared asfollows:

Example 13 A solution of 2.625 g. of penicillin-V in 30 m1. oftetrahydrofuran is mixed with 5.31 ml. of a 10 ml.-solution of 2 ml. oftriethylamine in tetrahydrofuran while stirring and cooling to 10. 3.6ml. of a 10 ml.-solution of 2 ml. of chloroformic acid ethyl ester intetrahydrofuran are then added slowly at 10 and after completion of theaddition, the mixture is stirred for minutes at 10 to --5.

The reaction mixture is treated with a solution of 0.51 g. of sodiumazide in 5.1 ml. of water, stirred for 30 minutes at 0 to 5 and dilutedwith 150 ml. of ice water. It is extracted three times with methylenechloride; the organic extracts are Washed with water, dried andevaporated at 25 and under reduced pressure. The amorphous penicillin-Vazide is thus obtained as a slightly yellowish oil; infrared absorptionspectrum (in methylene chloride): characteristic bands at 3.04 4.70;/.,5.61 5.82; (shoulder), 5.93 6.26 6.6 1, 6.71 8.50 and 9.40

A solution of 2.468 g. of penicillin-V azide in 30 ml. of benzene isheated to 70 for 30 minutes. The pure 2- iso cyanato 3,3 dimethyl 6(N-phenyloxyacetylamino)-4-thia-1-azabicyclo[3.2.0]heptan 7 one(configuration of 6-amino-penicillanic acid) can be obtained byevaporating the solution under reduced pressure; infra-red absorptionspectrum (in methylene chloride): characteristic bands at 3.03,u, 4.46,,5.59 5.93 7, 6-26/L, 6.62u, 6.70 7.53 14, 8.28;, 8.53 924a and 9.40 17.

The above solution of the 2-is0cyanato-3,3-dimethyl-6-(N-phenyloxyacetyl-amino) 4 thia-l-azabicyclo[3.2.0] heptan-7-one ismixed with 3.4 ml. of a 10 ml.-solution of 2 ml. of2,2,2-trichloroethanol in benzene and the reac-- tion mixture is keptfor minutes at 70. The solvent is removed under reduced pressure and theresidue is purified on 40 ml. of acid-washed silica gel (column). Using300 ml. of benzene and 300 ml. of a 9: l-mixture of benzene and ethylacetate, by-products are washed out and the pure2-(N-carbo-2,2,2-trichloroethoxy-amino)-3,3-dimethyl 6(N-phenyloxyacetyl-amino)-4-thia-1-azabicy- IIIH-C O CHzC Ch C CH-CH iseluted with 960 ml. of a 9:1-mixture of benzene and ethyl acetate. Afterrecrystallization from a mixture of ether and pentane, the product meltsat 169-171 (decomposition); [cc] =-|83 (c. =1.0l in chloroform); thinlayer chromatogram (silica gel): Rf=0.5 in a 1:1- mixture of benzene andethyl acetate; infra-red absorption spectrum (in methylene chloride):characteristic hands at 3.05 t, 5.62, 5.77 5.93m 6.27 t, 6.62 1, 6.70 0,8.30m 9.23 1. and 9.5Qu.

Instead of the above mentioned 2 (N rcarbo 2,2,2- trichloroethoxy-amino)3,3 dimethyl 6 (N-phenyloxyacetyl-amino) 4 thia 1azabicyclo[3.2.0]heptan- 7-one it is also possible to use as anintermediate, the corresponding 2(N-carbo-Z,Z-dichloroethoxy-amino)-3,3- dimethyl 6(N-phenyloxyacetyl-amino) 4 thia lazabicyclo[3.2.0]heptan-7-one(configuration of 6-aminopenicillanic acid) of the formula IiIH-C O OCHzCHCl:

I C 011- H \s/ \CHI Example 14 15 ml. of a sulfonic acid type of ionexchanger (H form) are converted to the triethylammonium salt form bytreatment with a solution of 5 m1. of triethylamine in 100 ml. of water,the column is washed with 300 ml. of water until neutral and treatedwith a solution of 2 g. of the sodium salt of penicillin-G in 10 ml. ofwater, and thereafter eluted with water. A total of 45 ml. is taken andthe solution is lyophilized at a pressure of 0.01 mm. Hg. The crudetriethylammonium salt of penicillin-G thus obtained is dissolved inmethylene chloride and the solution is dried over sodium sulfate,filtered and evaporated.

A solution of the penicillin-G triethylammonium salt obtainable in thismanner, in a mixture of 40 ml. of methylene chloride and 40 ml. oftetrahydrofuran, is cooled to -10 and slowly mixed with 2.9 ml. of a 10mL-solution of 2 ml. of chloroformic acid ethyl ester in tetrahydrofuranwhile stirring. The mixture is stirred for 90 minutes at 5 to 0, thenmixed with a solution of 0.395 g. of sodium azide in 4 m1. of water, andthe mixture is stirred for 30 minutes at 5 to 0. It is diluted with 100ml. of ice Water and extracted three times with 75 ml. of methylenechloride at a time; the organic extracts are washed with water, driedand evaporated at room temperature under reduced pressure. The amorphouspenicillin-G azide is thus obtained, infra-red absorption spectrum (inmethylene chloride): characteristic bands at 3.05 t, 4.71 i, 5.62 t,5.80 5.94/.L, 6.69 1; and 8.50 1.

A solution of 1.72 g. of the penicillin-G azide in 30 ml. of benzene ismixed with 1.5 ml. of 2,2,2-trichloroethanol and stirred for 25 hours at70. During the first min-.

utes a continuous evolution of nitrogen is observed and after a fewhours the product separates out from the solution. The mixture isdiluted with 60 ml. of hexane while stirring, cooled, and filtered after15 minutes. The filter residue is washed with a 2:1-mixture of benzeneand hexane and with cold ether. The pure 2-(N-carbo-2,2,2-trichloroethoxy-amino) 3,3 dimethyl 6 (N-phenylacetyl-amino) 4 thia 1azabicyclo[3.2.0]heptan-7- one (configuration of 6 amino-penicillanicacid) of the formula IIIH-CO OCHzC Ch M.P. 223-223.5, is thus obtained;[a] =+172 (c.=1.018 in ethanol); infra-red absorption spectrum (inmethylene chloride): characteristic bands at 3.04 1, 5.61 i, 5.77 1,6.57 1, 6.70 t, 830 9.17fL, 9.62 t and 11.85 t.

The product can also be obtained by warming 0.03 g. of penicillin-Gazide in 2 ml. of benzene to 70 for 20 minutes, and forming the2-isocyanato-3,3-dimethyl-6-(N-phenylacetyl-amino)-4-thia-1-azabicyclo[3.2.0] heptan 7- one(configuration of G-amino-penicillanic acid) by evaporating the reactionmixture under reduced pressure; infrared absorption spectrum (inmethylene chloride): characteristic bands at 3.06 r, 4.48 t, 5.625.96 1. and 6.7011; and converting this, in accordance with the processindicated in Example 13, by reaction with 2,2,2-trichloroethanol intothe desired 2-(N-carbo-2,2,2-trichloroethoxyamino)-3,3-dimethyl-6-(N-phenylacetyl-amino) -4-thia 1-azabicyclo[3.2.0]heptan-7-one (configuration of 6-aminopenicillanicacid).

Example 15 A suspension of 0.5 g. of crude 6-amino-penicillanic acid in4 ml. of chloroform (freshly distilled over phosphorus pentoxide) istreated with 1 ml. of hexamethyldisilazane of the formula [(CH Si] NI-Iand 1 ml. of chloroform (dried over phosphorus pentoxide); the reactionmixture is boiled under reflux for 2% hours with exclusion ofatmospheric .moisture, is then cooled to 0, and, after the addition of1.7 ml. of a 10 ml.-solution of 2 ml. of triethylamine in chloroform, istreated with 0.385 g. of distilled fluoroformic acid tert.-butyl ester.The mixture is kept for 30 minutes at 0 and then for minutes at roomtemperature and is diluted with cold methylene chloride. The organicsolution is washed with a cold 10% aqueous citric acid solution andwater, with the aqueous wash solutions being back-washed with coldmethylene chloride. The combined organic extracts are twice extractedwith a dilute aqueous sodium hydrogen carbonate solution and,immediately after separation, are acidified with citric acid in thepresence of methylene chloride and at 0. The organic phase is separated,dried and evaporated; the pure amorphous6-(N-carbo-tert.-butyloxy-amino)-penicillanic acid is thus obtained;infra-red absorption spectrum (in methylene chloride): characteristicbands at 3.04 t, 5.63 1, 5.82 t, 6.67 7.32 t and 8.60 4; and isimmediately used without purification.

The resulting 6-(N-carbo-tert.-butyloxy-amino)-penicil- 1anic acid isdissolved in 10 ml. of methylene chloride and treated with 0.43 ml. of a10 ml.-solution of 2 ml. of triet-hylamine in methylene chloride. Onevaporation the 6- (N-carbo-tert.-butyloxy-amino)-pencillanic acidtriethylammonium salt is obtained as an amorphorus residue; infra-redabsorption spectrum (in methylene chloride): characteristic bands at3.05 5.67 i, 5.85[.L, 6.17 i, 6.67 7.32 4 and 8.53 t.

A solution of 0.226 g. of the6-(N-carbo-tert.-butyloxyamino)-penicillanic acid triethylammonium saltin 5 ml. of tetrahydrofuran is mixed at 10 with 0.26 ml. of a 10ml.-solution of 2 ml. of chloroformic acid ethyl ester intetrahydrofuran. After stirring for 90 minutes at -5 to the mixture istreated with a solution of 0.04 g. of sodium azide in 0.4 ml. of water.The mixture is stirred for a further 30 minutes at 5 to 0 and is thendiluted with ml. of ice-water and extracted with methylene chloride. Theorganic extract is dried and evaporated under reduced pressure at atemperature below the crude6-(N-carbo-tert.-butyloxy-amino)-penicillanic acid azide is obtained asthe residue; infra-red absorption spectrum (in methylene chloride):characteristic bands at 3.03 4.70,u, 5.62a, 5.83,, 6.l6,u, 7.32 8.60 2and 9.40

The crude product obtained above is dissolved in 5 ml. of benzene,stirred for 5 minutes at 70, and a small amount of the solvent isevaporated; according to the infrared spectrum (in methylene chloride:characteristic bands at 3.03% 4.48/J., 5.61% 5.83;, 6.67% 7.31M, 7.55,uand 8.62 the rearrangement to give the2-isocyanato-3,3-dimethyl-6-(N-carbo-tert.-butyloxy-amino)-4-thia-1azabicyclo[3.2.0]heptan-7-one (configuration of 6-amino-penicillanicacid) is complete. The warm benzene solution is mixed with 0.2 ml. of2,2,2-trichloroethanol; the reaction mixture is stirred for a further 90minutes at 70 and is then evaporated under reduced pressure. TheZ-(N-carbo- 2,2,2-trichloroethoxy-amino)-3,3-dimethyl-6-(Ncarbotert.-butyloxy-amino)-4-thia-l azabicyclo[3.2.0]heptan- 7-one(configuration of -amino-penicillanic acid) of the formula NH-C OOCHiCCII is thus obtained as a crystalline product which afterrecrystallization from a mixture of ether and pentane melts at 165-167;infra-red absorption spectrum (in methylene chloride): characteristicbands at 3.04m, 5.63;, 5.81 5.8411, 6-69/-L, 7.34,u., 8.65% 9.16;; and9.59 .l..

Example 16 A solution of 3 g. of crystalline2-(N-carbo-2,2,2-trichloroethoxy-amino)-3,3-dimethyl 6 (Nphenyloxyacetyl-amino)-4-thia-l-azabicyclo[3.2.0]heptan-7 one in 65 ml.of 90% aqueous acetic acid and ml. of dimethylformamide is mixed with32.6 g. of zinc dust over the course of 20 minutes while cooling withice, and is stirred for 20 minutes. The excess zinc is filtered off andthe filter residue is washed with benzene; the filtrate is diluted with450 ml. of benzene, washed with a saturated aqueous sodium chloridesolution and with water, dried an evaporated under reduced pressure. Theresidue is purified on a column of 45 g. of acid-washed silica gel.Elution is carried out with 100 ml. of benzene and 400 ml. of a 9: 1-mixture of benzene and ethyl acetate and apolar products are obtained.Starting material is eluted with 100 ml. of a 4:1-mixture of benzene andethyl acetate, and with a further 500 ml. of the 4:1-mixture of benzeneand ethyl acetate and with 200 ml. of a 2: l-mixture of benzene andethyl acetate 2-hydroxy-3,3-dimethyl-6 (Nphenyloxyacetyl-amino)-4-thia-l-azabicyclo[3.2.0]heptan 7 one(configuration of 6-amino-penicillanic acid) of the formula is obtained;this crystallizes spontaneously as the hydrate and after triturationwith ether, saturated with water, melts in an unsharp manner in therange of 62-85.

If chromatographed but non-crystalline starting material is used and thereduction is carried out in dilute acetic acid without the addition ofdimethylformamide, the pure product, M.P. 62-70", is obtained; thinlayer chromatogram (silica gel): Rf=0.35 in a lzl-mixture of benzene andethyl acetate; infra-red absorption spectrum (in methylene chloride):characteristic bands at 2.93 2, 3-09/L, 5.65 5.96 629g, 6.65 6.75p.,8.57 9.27 10.00; and 11.951.6-

Example 17 A solution of 2.49 g. of2-(N-carbo-2,2,2-trichloroethoxy-amino) 3,3dimethyl-6-(N-phenylacetyl-amino)-4-thia-l-azabicyclo[3.2.01heptan-7-one in 50 ml. of dimethylformamide,25 m1. of acetic acid and 5 ml. of water is prepared at roomtemperature, and is then cooled to 0 and mixed with a total of 25 g. ofzinc dust over the course of 10 minutes while stirring. The mixture isleft for 20 minutes at 0, and is then filtered into a receivercontaining 500 ml. of a saturated aqueous sodium chloride solution, andthe filter residue is washed with 25 ml. of acetic acid. The filtrate isextracted three times with 300 ml. of benzene at a time; the organicextracts are washed with water, a dilute aqueous sodium hydrogencarbonate solution and water, combined, dried and evaporated underreduced pressure. The residue is chromatographed on 45 g. of acid-washedsilica gel. Fractions of ml. each are taken, elution being carried outwith 300 ml. of benzene, 300 ml. of a 911-, 500 ml. of a 4:1-, 600 ml.of a 2:1- and 200 ml. of a lzl-mixture of benzene and ethyl acetate and100 ml. of ethyl acetate. Fractions 8 and 9 contain crystalline startingmaterial, while the 2-hydroxy-3,3-dimethyl 6(N-phenylacetyl-amino)-4-thia-1-azabicyclo [3.2.0]heptan-7-one(configuration of fi-amino-penicillanic acid) of the formula C CH-CH isobtained as a colorless oil from fractions 11-15; infrared absorptionspectrum (in methylene chloride): charactenstic bands at 2.90;, 3.05,,5.64n, 5.99;, 6.7014 and 9.28,u.

Example 18 A solution of 0.5 g. of2-(N-carbo-2,2,2-trichloroethoxy-amino)3,3-dimethyl-6-(N-carbo-tert.-butyloxyamino)4-thia-1-azabicyc1o[3.2.0]heptan-7-one (configuration of6-amino-penicillanic acid) in 5 ml. of tert.- butanol is diluted with 4ml. of acetic acid and 1 ml. of water. After cooling in an ice bath, 5g. of zinc dust are added in small portions over the course of 15minutes while stirring. The mixture is stirred for a further 30 min- 21heptan-7-one (configuration of 6-amino-penicillanic acid) of the formulabeing then eluted as a colorless oil with the same solvent mixture andwith a 4:1-mixture of benzene and ethyl acetate. This materialcrystallizes from a mixture of ether and pentane, M.P. 106-110(sintering from 100 up); [a] =ll5 i1 (c.=0.858 in chloroform); thinlayer chromatogram (silica gel); Rf-0.53 in a lzl-mixture of benzene andethyl acetate; infra-red absorption spectrum '(in methylene chloride):characteristic bands at 2.911s,

3.04 5.64 1, 5.84 4, 6.68 7.33 1 and 8.60 1.

Example 19 A solution of 0.065 g. of 2-hydroxy-3,3-dimethyl-6-(N-phenyloxyacetyl-amino) 4 thia-l-azabicyclo[3.2.0]heptan-7-one(configuration of 6-amino-penicillanic acid) in ml. of benzene istreated with 0.15 g. of lead tetraacetate containing of acetic acid, andthe yellow solution is irradiated by means of a high pressure mercuryvapour lamp (80 watts) in a water-cooled Pyrex glass jacket. After 10minutes the yellow color disappears and a partially fiocculent andwhite, partially gum-like and yellow precipitate forms. The mixture isdiluted with benzene, washed with water, a dilute aqueous sodiumhydrogen carbonate solution and water, and evaporated under reducedpressure pressure. The 1-formyl-2a-(Z-acetyloxy- 2-propyl-mercapto) 3a(N-phenyloxyacetyl-amino)- azetidin-4-one of the formula err-on CH:@o-om-p-nia 's- -op-cm is thus obtained as a slightly yellowish gum-likeproduct; infra-red absorption spectrum (in methylene chloride):characteristic bands at 3.05;, 5.56;, 5.78;, 5.90;, 6.27;, 6.62;, 6.7173311., 7.6711,, 8.9211, 9.2411. and 9132p.

Example A solution of 0.1 g. of 2-hydroxy-3,3-dimethyl-6-(N-phenylacetyl-amino) 4 thia 1 azabicyclo[3.2.0]heptan-7-one(configuration of G-amino-penicillanic acid) in 10 ml. of benzene istreated with 0.24 g. of lead tetraacetate containing 10% of acetic acid,and the yellow mixture is irradiated, while stirring at 10, by means ofa high pressure mercury vapour lamp (80 watts) in a water-cooled Pyrexglass jacket. After 20 minutes no further tetravalent lead compound canbe detected and the reaction mixture is colorless, with a yellowishprecipitate having settled on the walls of the vessel. The mixture isdiluted with benzene, washed with water and a dilute aqueous sodiumhydrogen carbonate solution and evaporated under reduced pressure at atemperature below The amorphous1-for-myl-2u-(2-acetyloxy-2-propylmercapto)-3a-(N-iphenylacetyl-amino)-azetidin-4-oneof the formula O=C-NCHO on-en CH3 @OHr-C-NEI "s-o-o-c-on,

ll a.

is thus obtained; infra-red absorption spectrum (in methylene chloride):characteristic bands at 3.04 5.56 1, 5.78p., 5.875 6.69% 7.331., 7.68m8.57 1, 8.93 1. and 934g.

22 Example 21 A solution of 0.3 g. of 2-hydroxy-3,3-dimethyl-6-(N-carbo-tert.-butyloxy-amino)-4-thia l azabicyclo[3.2.0] heptan-7-one(configuration of fi-amino-penicillanic acid) in 125 ml. of anhydrousbenzene is mixed with l g. of vacuum-dried lead tetraacetate and 0.09ml. of pyridine and the mixture is irradiated at about 12l5 with a highpressure mercury vapour lamp (Hanan; type Q 81; Watts) in a water-cooledPyrex glass jacket, while keeping it agitated by passing a stream ofoxygen-free nitrogen through it. A white precipitate of lead diacetateforms; a small quantity of a gum-like black product which very probablycontains metallic lead deposits on the Pyrex glass jacket and is scrapedoff from time to time. After 1 hour the entire quantity of leadtetraacetate has been consumed; the mixture is filtered and the filtrateis washed with a dilute aqueous sodium hydrogen carbonate solution andwith water, dried and evaporated under reduced pressure. The crude1-formyl-2 z (2-acetyloxy-2-propylmercapto) 3oz(N-carbo-tert.-butyloxy-amino)-azetidin- 4-one of the formula I 111.cH-on CH3 3 H30 1 C-0C-NH 's-o-o-o-orn H3 CH3 is obtained as anamorphous product and is further processed without purification;infra-red absorption spectrum (in methylene chloride): characteristicbands at 3.04 5.56 1, 5.88 6.70;, 7.33 1 and 8.70

Example 22 A solution of 0.5 g. of the hydrate of 2-hydroxy-3,3-dimethyl-6-(N-phenyloxyacetyl-amino)-4-thia 1azabicyclo[3.2.0]heptan-7-one (configuration of 6-amin0-penicillanicacid) in 125 ml. of anhydrous benzene is treated with 1.15 g. of leadtetraacetate (containing 10% of acetic acid) and the mixture isirradiated at about 15 with a high pressure mercury vapour lamp (80watts) in a water-cooled Pyrex glass jacket, with a slow stream ofoxygen-free nitrogen being passed through. After 1% hours the originallyyellow solution becomes colorless; the reaction on potassiumiodide-starch paper is negative. The reaction mixture is filtered andthe filtrate is diluted with benzene and washed with water, a diluteaqueous sodium hydrogen carbonate solution and water, dried andevaporated under reduced pressure. The residue contains thel-formyl-Za-(2-acetyloxy-2-propyl-mercapto)-3u-(Nphenyloxyacetyl-amino)-azetidin 4 one which is further processed withoutpurification.

Example 23 A solution of 1 g. of the hydrate of2-hydroxy-3,3-dimethyl-6- (N-phenyloxyacetyl-amino -4-thial-azabicyclo-[3.2.0]heptan-7-one (configuration of -amino-penicillanic acid) in 125ml. of anhydrous benzene is treated with 0.3 ml. of pyridine and 2.6 g.of lead tetraacetate which has been dried under reduced pressure; themixture is irradiated at about 15 with a high pressure mercury vapourlamp (80 watts) in a water-cooled Pyrex glass jacket, with a slow streamof nitrogen (pyrogallolwashed) being passed through. After 3 hours thetest on potassium iodide-starch paper is only slightly positive. Themixture is filtered, washed with ml. of a dilute aqueous sodium hydrogencarbonate solution and 100 ml. of water, dried and evaporated underreduced pressure; the crude product contains the1-formyl-2a-(Z-acetyloxy- 2-propylmercapto)-3u-(N-phenyloxyacetyl-amino)-azctidin-4-one, which is furtherprocessed without purification.

Example 24 A solution of 0.5 g. of the hydrate of 2-hydroxy-3,3-dimethyl-6-(N-phenyloxyacetylamino)-4-thia-l-azabicyclo[.3.2.0]heptan-7-one (configuration of6-amino-pencillanic acid) and 2.1 g. of lead tetrabenzoate in 160 m1. ofanhydrous benzene, through which is a stream of oxygen-free nitrogen ispassed, is irradiated with a high pressure mercury vapour lamp (Hanan Q81; 70 watts) at 15 in a water-cooled Pyrex glass jacket. The originallydark yellow solution becomes colorless after about 1 /2 hours; only asmall quantity of a fiocculent precipitate forms which is filtered oif.The filtrate is washed with water, a dilute aqueous sodium hydrogencarbonate solution and again with water, dried and evaporated underreduced pressure. The residue containing thel-formyl-2a-(2-benzoyloxy-Z-propyl-mercapto)-3a-(Nphenyloxyacetyl-amino)-azetidin-4-one of the formula =C-NCHO is furtherprocessed without purification.

Example 25 A solution of 0.18 g. of 2-hydroxy-3,3-dimethyl-6-(N-phenyloxyacetyl-amino)-4-thia 1 azabicyclo[3.2.0]heptan-7-one hydrate(configuration of -amino-penicillanic acid) in ml. of tetrahydrofuran ismixed at 0 with 0.3 ml. of a solution of 0.38 g. of sodium borohydridein 5 ml. of water. The mixture is stirred for minutes at 0, thenadjusted to pH- 4 by adding 12 drops of acetic acid and is diluted with50 ml. of methylene chloride. The organic solution is twice washed witha saturated aqueous sodium chloride solution, the aqueous solutions areback-washed with methylene chloride and the combined organic solutionsare dried and evaporated under reduced pressure. The crystalline residueis recrystallized from a mixture of methylene chloride and ether,whereupon the 2a-(Z-hydroxymethyl-2-propyl-mercapto)-3a-(N-phenyloxyacetylamino)-azetidin-4-one of the formula O=CNH err-onom 0-oH.-o-Nit "s-o-oHtoH (H) OH:

is obtained which after repeated recrystallization is obtained inneedles, MP. 156-157"; [a] =+130:L-1 (c.=0.708 in chloroform); infra-redabsorption spectrum (in methylene chloride): characteristic bands at3.03 5.65/L, 5.94 6.26p., 6.58 6.70,u, 8.15 8.27 11 and 9.43g.

Example 26 A suspension of 0.08 g. of 2a-(2-hydroxymethyl-2-propyl-mercapto) 3oz (N phenyloxyacetyl-amino)- azetidin-4-one in ml. ofanhydrous benzene is treated with 0.3 g. of lead tetraacetate containing10% of acetic acid and irradiated at about 10 with a high pressuremercury vapour lamp (80 watts) in a water-cooled Pyrex glass jacket,while stirring. After 45 minutes, no further tetravalent lead compoundcan be detected with potassium iodide-starch paper. The precipitateforming on the walls of the vessel during the reaction is scraped offfrom time to time. 1 g. of polystyrene-Hiinig base (manufactured bywarming a mixture of 100 g. of chloromethyl polystyrene [1. Am. Chem.Soc. 85, 2149 (1963)], 500 ml. of benzene, 200 m1. of methanol and 100m1. of diisopropylamine to 150 while shaking, filtering, Washing with1000 ml. of methanol, 1000 ml. of a 3:1-rnixture of dioxane andtriethylamine, 1000 ml. of methanol, 1000 ml. of dioxane and 1000 ml. ofmethanol, and drying for 16 hours at 100/100 mm. Hg; the productneutralizes 1.55 milliequivalents of hydrochloric acid per 1 g. in a 2:l-mixture of dioxane and water) is added to the mixture, which isstirred for 5 minutes and filtered, and the filtrate is evaporated atabout -40 under reduced pressure. The residue contains the2a-(2-acetyloxy-Z-propylmercapto)-3-(N phenyloxyacetyl-amino)-azetidin-4-one of the formula which is processed witout additionalpurification.

The Zea-(2 hydroxymethyl 2 propylmercapto)-3a-(N-carbo-tert.-butyloxy-amino)-azetidin-4-one can be converted to the2a-(2 acetyloxy 2 propylmercapto)-3a.-(N-carbo-tert.-butyloxyamino)-azetidin-4-one in a similar manner bytreatment with lead tetraacetate.

The resulting compounds may be used as starting materials in thefollowing manner:

Example 27 A mixture of 0.1 g. of l-formyl 2a isopropenylmercapto 304(N-phenyloxyacetyl-amino)-azetidin-4- one in 5 ml. of ethyl acetate ishydrogenated for 1 hour in the presence of 0.2 g. of a 10%palladium-on-charcoal catalyst and is then filtered, and the filtrate isevaporated under reduced pressure. The residue is purified bychromatography on 5 g. of acid-washed silica gel and the 1- formyl 2ozisopropyl-mercapto 3a (N-phenyloxyacetyl-amino)-azetidin-4-one of theformula O CH1 is eluted with a 4: l-mixture of benzene and ethylacetate. 30% of the resulting product is starting material; theinfra-red absorption spectrum (in methylene chloride) showscharacteristic bands at 3.04 5.56 1,, 589 6.26,u, 6.63;], 6.724s and7.67,u.

Example 28 A mixture of 0.5 g. of a 10% palladium-on-charcoal catalystin 5 ml. of ethyl acetate is pre-hydrogenated at 25 in the course ofwhich 14.3 ml. of hydrogen are taken up. 0.063 g. of l-formly 2o:isopropenylmercapto- 3a-(N-phenylacetylamino)-azetidin 4 one in 2 ml. ofethyl acetate are then added and the mixture is further hydrogenated for2% hours at 30. After filtering and evaporating the solvent, the residueis chromatographed on 5 g. of acid-washed silica gel. By-products areeluted with 10 ml. of benzene and 10 ml. of a 4:1-mixture of benzene andethyl acetate and with a further 15 ml. of the same mixture the l-formyl2a isopropylmercapto- 3m (N-phenylacetyl-amino)-azetidin 4 one of theformula CHa is obtained as a colorless oil which shows characteristicbands at 3.04 556 5.92 6.18;, 7.24 and 7.68p., in the infra-redabsorption spectrum (in methylene chloride).

Example 29 A solution of 0.08 g. of 2a-isopropenylmercapto-3a(N-phenyloxyacetyl-amino)-azetidin-4-one in 10 ml. of ethyl acetate isstirred for minutes in the presence of 0.1 g. of a 10%palladium-on-charcoal catalyst, in a hydrogen atmosphere; the absorptionof the hydrogen ceases after about 25 minutes. The reaction mixture isfiltered and the filtrate is evaporated. The crystalline residue isrecrystallized from a mixture of methylene chloride and ether; theresulting 2a isopropylmercapto 3oz (N-phenyloxyacetyl-amino)-azetidin-4-one of the formula melts at 128130 and143 (double melting point); infra-red absorption spectrum (in methylenechloride): characteristic bands at 3.05 5.63 5.93 t, 6.26 6.58 6.70;,8.15;, 9.21 and 9.41

Example 30 is obtained as a colorless oil which crystallizes on additionof benzene and melts at 115-1 17 after recrystallization from benzene;[a] =+8i1 (c.=0.845 in chloroform); thin layer chromatography (silicagel; system: 1:1- mixture of benzene and ethyl acetate): Rf=0.13;infrared absorption spectrum (in methylene chloride): characteristicbands at 2.95 t, 5.68 1. (potassium bromide) and 5.78,u..

Example 31 A solution of 0.15 g. of 4,4-dimethyl-azetidino[3.2-d]thiazolidin-Z-one in 10 ml. of dry tetrahydrofuran (freshly filteredthrough a column of aluminum oxide, activity I) is cooled to Phosgene ispassed through the cold solution for 5 minutes and the reaction mixtureis stirred for a further 30 minutes and with the exclusion ofatmospheric moisture; the precipitate which initially appearsredissolves. The mixture is then evaporated and the residue ischromatographed on 3 g. of acid-washed silica gel. The desired 3chlorocarbonyl-4,4-dimethyl-azetidino[3.2-d] thiazolidin-Z-one of theformula is eluted with benzene and with a 9: l-mixture of benzene Asolution of 0.1 g. of3-chlorocarbonyl-4,4-dimethylazetidino[3.2-d1thiazolidin-2-one in 10 ml.of tert.-butanol is mixed with 0.2 g. of calcium carbonate and heated ina closed vessel for 2 /2 days at bath temperature While stirring. Aftercooling the mixture is filtered, the residue is washed with benzene andthe filtrate is evaporated under reduced pressure. The residue is takenup in benzene; the organic solution is washed with water, dried andagain evaporated. The residue is again dissolved in benzene andchromatographed on 1 g. of acid-washed silica gel. The 3carbo-tert.-butyloxy 4,4-dimethyl-azetidino [3.2-d1thiazolidin-2-one ofthe formula We claim: 1. A compound of the formula O=C--NRz JH H CH2Ac-NH SC\ in which Ac is a member selected from the group consisting oflower alkanoyl having up to 8 carbon atoms, lower alkenoyl having up to8 carbon atoms, phenylacetyl, phenyloxyacetyl, carbo-lower alkoxy,carbo-adamantyloxy, carbo-phenyl-lower alkoxy and carbofuryl-loweralkoxy, each of said lower alkoxy moieties having 1 to 7 carbon atoms,and R stands for a member selected from the group consisting of hydrogenatom and a formyl group.

2. A compound as claimed in claim 1 and being 1-formyl-2a-isopropenylmercapto 3oz (N-phenyloxyacetylamino)-azetidine-4-one.

3. A compound as claimed in claim 1 and being 1- formyl 2aisopropenylmercapto 3w (N-phenyl-acetylamino)-azetidine-4-one.

4. A compound as claimed in claim 1 and being 1- formyl2ot-isopropenylmercapto-3u-(N-carbo-tert.-butyloxy-amino)-azetidine-4-one.

5. A compound as claimed in claim 1 and being 2a-isopropenylmercapto 3oz(N-carbo-tert.-butyloxy-amido)- azetidine-4-one.

6. A compound as claimed in claim 1 and being 2a-isopropenylmercapto3a-(N-phenyloxyacetyl-amino)-azetidine-4-one.

No references cited.

ALEX MAZEL, Primary Examiner J. TOVAR, Assistant Examiner U.S. Cl. X.R.

